Field of the Invention
The present invention is generally directed to novel PKM2 modulators and use of the same for treatment of various cancers.
Description of the Related Art
Proliferation of cancer cells requires the accumulation of sufficient biosynthetic building blocks (i.e., biomass) to replicate each nucleic acid, protein and lipid in the cell. As a tumor grows, the need for nutrients and oxygen can exceed the capacity of poorly vascularized blood vessels. Faced with such challenges, cancer cells must be able to adjust metabolic pathways.
Glucose provides cancer cells with building blocks in the form of glycolytic pathway intermediates (Mazurek S., Int. J. Biochem. Cell. Biol. 43(7):969-80 (2010); Vander Heiden M. G., Cantley L. C., Thompson C. B., Science 324(5930):1029-33 (2009)). The main enzyme regulating flux through the glycolitic pathway in cancer cells, and thus the level of available intermediates, is the M2 splice form of pyruvate kinase (PKM2), which controls the rate-limiting final step in glycolysis. PKM2 is allosterically regulated by fructose-1,6-bisphosphate (FBP), an upstream glycolytic intermediate that binds to and converts PKM2 from a less active dimeric form with low affinity for its substrate, phosphoenolpyruvate (PEP), to an active tetrameric form with high PEP affinity (Ashizawa K., Willingham M. C., Liang C. M., Cheng S. Y., J. Biol. Chem. 266(25):16842-46 (1991); Mazurek S., Boschek C. B., Hugo F., Eigenbrodt E., Semin. Cancer Biol. 15(4):300-08 (2005)). When glucose is abundant, FBP levels increase and PKM2 is activated, leading to high glycolytic flux. When glucose is limiting, FBP levels decrease and PKM2 is inactivated, allowing upstream glycolytic intermediates to accumulate and be diverted into biosynthetic pathways (Mazurek S., Michel A., Eigenbrodt E., J. Biol. Chem. 272(8):4941-52 (1997)).
PKM2 is upregulated in cancer cells (Altenberg B., Greulich K. O., Genomics 84(6): 1014-20 (2004)), and has been shown to increase tumorigenicity compared to the alternatively spliced and constitutively active PKM1 isoform (Christofk H. R., Vander Heiden M. G., Harris M. H., et al., Nature 452(7184):230-33 (2008); Goldberg M. S., Sharp P. A., J. Exp. Med. 209(2):217-24 (2012)). Specific RNAi knockdown of PKM2 has also been shown to regress established xenograft tumors (Goldberg M. S., Sharp P. A., J. Exp. Med. 209(2):217-24 (2012)). These findings indicate that control of glycolytic flux through PKM2 activation/inactivation is important for tumor growth.
PKM2 has recently been shown to have a critical function in regulating serine biosynthesis. Serine is synthesized de novo from glycolytic intermediate 3-phosphoglycerate, and serine itself is used in the synthesis of nucleotides, proteins, lipids, and glutathione (Locasale J. W., Cantley L. C., Cell Cycle 10(22):3812-13 (2011)). When serine is absent from the growth media, PKM2 expressing cells reduce glycolytic flux (presumably through PKM2 inactivation) and accumulate glycolytic intermediates such as 3-phosphoglycerate. This allows PKM2 expressing cells to proliferate in serine-depleted media to a significantly greater degree than cells expressing PKM1 (Ye J., Mancuso A., Tong X., et al. Proc. Nat'l Acad. Sci. U.S.A. 109(18):6904-09 (2012)). Serine, like FBP, is an allosteric activator of PKM2 (Eigenbrodt E., Leib S., Kramer W., Friis R. R., Schoner W., Biomed. Biochem. Acta. 42(11-12):S278-82 (1983)). It is thus likely that when cellular serine levels are sufficiently high, PKM2 is converted to the active tetrameric form, restoring glycolytic flux to lactate.
Cancer cells inactivate PKM2 through multiple mechanisms, including oncoprotein binding (Kosugi M., Ahmad R., Alam M., Uchida Y., Kufe D., PLoS One 6(11):e28234 (2011); Zwerschke W., Mazurek S., Massimi P., Banks L., Eigenbrodt E., Jansen-Durr P., Proc. Nat'l Acad. Sci. U.S.A. 96(4):1291-96 (1999)), tyrosine phosphorylation (Hitosugi T., Kang S., Vander Heiden M. G., et al., Sci. Signal 2(97):ra73 (2009); Presek P., Glossmann H., Eigenbrodt E., et al., Cancer Res. 40(5): 1733-41 (1980); Presek P., Reinacher M., Eigenbrodt E., FEBS Lett. 242(1):194-98 (1988)), lysine acetylation (Lv L., Li D., Zhao D., et al., Mol. Cell 42(6):719-30 (2011)), cysteine oxidation (Anastasiou D., Poulogiannis G., Asara J. M., et al., Science 334(6060):1278-83 (2011)), and prolyl hydroxylation (Chen N., Rinner O., Czernik D., et al., Cell Res. 21(6):983-86 (2011)). In each case, decreased PKM2 activity correlates with increased tumorigenicity. It was recently shown that PKM2 mutations that inhibit tetramerization also increase tumorigenicity (Gao X., Wang H., Yang J. J., Liu X., Liu Z. R., Mol. Cell 45(5):598-609 (2012)). In light of such evidence, efforts have focused on the discovery and development of small molecule PKM2 activators (Boxer M. B., Jiang J. K., Vander Heiden M. G., et al., J. Med. Chem. 53(3):1048-55 (2010); Jiang J. K., Boxer M. B., Vander Heiden M. G., et al., Bioorg. Med. Chem. Lett. 20(11):3387-93 (2010); Walsh M. J., Brimacombe K. R., Veith H., et al., Bioorg. Med. Chem. Lett. 21(21):6322-27 (2011)) as a potentially useful anti-cancer therapy for treatment of sarcoma, brain, colorectal, kidney, head and neck, lung, ovarian, pancreatic and prostate cancers. PKM2 activators can also be used in combination of chemotherapeutic agent(s) to treat the above conditions.
While progress has been made in this field, there remains a need in the art for improved PKM2 modulators (e.g., activators), which are useful for treatment of any number of cancers. The present invention fulfills this need and provides further related advantages.